PROJECT SUMMARY As the prevalence of late-onset Alzheimer?s disease continues to increase, understanding the mechanistic causes of this disease is becoming increasingly critical. Recent clinical studies have linked increased stiffness of the large arteries to both impaired memory and Alzheimer?s disease. It is hypothesized that these relations are a result of large artery stiffness-induced cerebrovascular dysfunction. Increased large artery stiffness leads to greater pulsatility of pressure and blood flow in the cerebral vasculature, which is known to cause vascular damage. Dysfunction of the cerebral arteries and microvasculature is associated with cognitive impairment and greater Alzheimer?s disease-related neuropathology. Furthermore, amyloid-? (A?) induces cerebrovascular damage, and cerebrovascular impairment increases A? accumulation, thus creating a vicious cycle of cerebrovascular dysfunction and neuropathology. The goal of the proposed studies is to provide the first proof- of-concept evidence that age-related increases in large artery stiffness, synergistically with greater A? production, lead to cognitive impairment, neuropathology, and cerebrovascular dysfunction. To accomplish this goal, we will employ transgenic mouse models of greater large artery stiffness and greater A? production, as well as use a pharmacological intervention to prevent age-related increases in large artery stiffness. In Aim 1, we will assess the effects of large artery stiffness, in combination with A?, on cognitive dysfunction and Alzheimer?s disease-related neuropathology. In Aim 2, we will determine the effect of large artery stiffness, in combination with A?, on cerebral blood flow and cerebral vascular reactivity and structural integrity. In Aim 3, we will identify candidate mechanisms by which large artery stiffness and greater cerebral artery pulsatility lead to cerebrovascular dysfunction. To do so, we will examine the role and source(s) of vascular oxidative stress, as well as perform transcriptome analysis of cerebral arteries and microvascular endothelial cells. The knowledge to be gained by completing the proposed aims will inform future studies to identify novel therapeutic targets for the prevention or attenuation of late-onset Alzheimer?s disease.